Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use

ABSTRACT

Controlled release ceramic particles, processes for their preparation, controlled release ceramic particles prepared by such processes, compositions comprising such controlled release ceramic particles and methods of using controlled release ceramic particles are described. In one form each of the controlled release ceramic particles has an active material(s) substantially homogeneously dispersed throughout the particles, wherein the active material(s) is capable of being released from said particles, and the active material(s) in said particles is substantially protected from degradation until release of the active material(s) from the particles.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a Divisional of U.S. application Ser. No. 10/204,462filed Aug. 21, 2002, which is a National Stage of PCT/AU01/000173 filedFeb. 21, 2001, which claims priority to Australian Application PQ5733filed Feb. 21, 2000, all of which are incorporated herein by referencein their entirety.

TECHNICAL FIELD

This invention relates to controlled release ceramic particles,substantially monodispersed controlled release ceramic particles,processes for preparing substantially monodispersed controlled releaseceramic particles, substantially monodispersed controlled releaseceramic particles prepared by such processes, compositions comprisingcontrolled release ceramic particles according to the invention andmethods of using controlled release ceramic particles according to theinvention.

BACKGROUND ART

Current strategies for drug encapsulation and controlled releasetypically use organic vehicles such as polymers, liposomes and micelles.

(a) Polymeric systems can be broadly classified as:

Inert Matrix systems where the drug is trapped inside an inert,non-degradable polymer matrix, and its release controlled by diffusionthrough the porous network. In-vivo administration of suchnon-biodegradable polymeric particles is limited by the fact that thepolymers will concentrate in intracellular “pockets” (e.g. lysosomes) ortissue, inducing severe overload of non-metabolised material. Thislimits their use to trans-dermal patches, etc. Another significantlimitation is that the release is non-specific, since it is notactivated by specific sites within the body. Finally, drug moleculesexhibit intrinsically small diffusion coefficients within such matrices,limiting their broad application to potent drugs.

Reservoir systems, where the active ingredient's release is controlledby diffusion through an encapsulating membrane, hollow fibre, etc. Thekey limitations of these systems are their low mechanical strength andchemical resistance, since the controlling membrane is relativelyfragile and easily fouled.

Chemical systems, in which the active molecules are dispersed inside abiodegradable matrix (e.g. polymers such as polyorthoesters andpolyanhydrides). The release rate is preferably controlled by theheterogeneous (surface) dissolution/degradation of the matrix. Thisrestricts the range of polymers that can be employed as matrices tobioerodible polymers such as poly(glycolic acid), poly(DL) lactic acid,poly(glycolic-colactic acid), poly caprolactone, polyhydroxy butyrate,and poly dioxianone.

Solvent-activated systems (hydrogels), in which the matrix swells in thepresence of specific solute/solvent systems, with subsequent release ofthe encapsulated species. However, such polymers often swell too rapidlyto provide therapeutically useful release rates, and the development ofthese systems is still in its infancy. In such controlled deliverysystems, the delivery is controlled either by matrix structure (e.g.pore network tortuosity), particle size, overall drug loading or matrixsolubility. A limitation of polymeric systems is that they can typicallyonly exploit one, or at most two, of these features, and any changes inthe drug usually necessitates reformulation of the matrix system. Incontrast, an important feature of the present invention is that all ofthese features can be manipulated using the same underlying chemistry,which provides a more generic approach to designing controlled releasematrices for specific applications.

Moreover, while there are many polymeric materials that have beenidentified as having potential for controlled drug release, relativelyfew have been approved for use in either human or veterinarypharmaceutical products.

(b) Liposomes are the most highly developed carrier system, but sufferfrom problems with in-vivo stability, aging and limited shelf life.

(c) The thermodynamic instability of micelles (which depends ontemperature, concentration, solution speciation, etc) limits theirapplicability for controlling release. They also exhibit intrinsicallylow drug loading

(d) Bioceramics are used in bone-repair procedures (inert bioceramics,porous active ceramics that promote osteo-reconstruction). The inertbioceramics have purely mechanical applications, e.g. hip-joints(because of their low coefficient of friction)-typically Al₂O₃ or Y-TZP.The porous ceramics (typically hydroxy apatites) serve as structuralbridges and “scaffolds” for bone formation. Bioactive glass provides aninterfacial layer for tissues growth that resists substantial mechanicalforces. Bioactive glasses have also been proposed as matrices for thecontrolled delivery of bioactive substances.

Various patents have been issued to matrices prepared by sol-gel basedprocesses, for example:

U.S. Pat. No. 5,591,453 (awarded Sep. 1, 1997) discloses the use ofsol-gel silica matrices for the controlled release of biologicallyactive molecules. The application cited was for osteo-reconstruction,and was restricted to large gel monoliths or granules (typically 0.5 to5 mm). The release is controlled either by drug loading or varying thesurface to volume ratio. Possible interactions between the matrix anddrug were ignored. British Patent 1 590 574 (awarded Mar. 6, 1981)discloses the concept of incorporating biologically active components ina sol-gel matrix. Embodiment as substantially spherical particles in thesize range from several microns to several millimetres was envisaged. Itwas noted that the rate of release of the biologically active componentfrom the matrix would depend on a number of factors, including the pH ofthe medium, size of particles, and composition/porosity/structure/watercontent/hydrophilicity of the gel. The only example given was ofspray-dried particles produced from bohemite sols, from which all of theimipramine initially encapsulated was released within five minutes. WO9745367 (issued Apr. 12, 1997) discloses controllably dissolvable silicaxerogels prepared via a sol-gel process, into which a biologicallyactive agent is incorporated by impregnation into pre-sintered particles(1 to 500 μm) or disks. The release was controlled by varying thedimensions and chemical composition of the xerogels. WO 0050349 (issued31 Aug. 2000) discloses controllably biodegradable silica fibresprepared via a sol-gel process, into which a biologically active agentis incorporated during synthesis of the fibre. The release was primarilycontrolled by varying the dissolution rate of the fibres.

OBJECTS OF INVENTION

Objects of the invention are to provide controlled release ceramicparticles, substantially monodispersed controlled release ceramicparticles, processes of preparing substantially monodispersed controlledrelease ceramic particles, substantially monodispersed controlledrelease ceramic particles prepared by such processes, compositionscomprising such controlled release ceramic particles and methods ofusing such controlled release ceramic particles.

DESCRIPTION OF INVENTION

According to an embodiment of this invention there is providedcontrolled release ceramic particles, wherein each of said particles hasan active material(s) substantially homogeneously dispersed throughoutthe particles and wherein the active material(s) is capable of beingreleased from said particles.

The controlled release ceramic particles may be functionalised orderivatised.

According to another embodiment of this invention there is providedcontrolled release ceramic particles, wherein each of said particles hasan active material(s) substantially homogeneously dispersed throughoutthe particles, wherein:

-   -   (a) the active material(s) is capable of being released from        said particles; and    -   (b) the active material(s) in said particles is substantially        protected from degradation until release of the active        material(s) from the particles.

In other words, in the above embodiment each of the particles has anactive material substantially homogeneously dispersed throughout theparticle wherein the active material is capable of being released fromthe particle and the active material in the particles is incorporatedwithin the particles so as to be substantially protected fromdegradation until release of the active material from the particles.

During fabrication of the particles surfactant is typically removed fromthe particles so that they contain less than about 2 wt % surfactant,typically between 0.1-2 wt %, more typically 0.5-2 wt %, even moretypically between 1-2 wt %.

Typically ceramic particles comprise an oxide selected from the groupconsisting of silica, zirconia, alumina and titania.

The controlled release ceramic particles of the invention may beadvantageously prepared by a sol gel process.

The ceramic particles may be in the form of freeze dried particles oralternatively they may be dispersed in solution. Typically when theparticles are in the form of freeze dried particles they are mixed withor in a matrix with an ionic salt.

According to one embodiment of this invention there is providedsubstantially monodispersed controlled release ceramic particles,wherein each of said particles has an active material(s) substantiallyhomogeneously dispersed throughout the particles and wherein the activematerial(s) is capable of being released from said particles.

The substantially monodispersed controlled release ceramic particles maybe functionalised.

The substantially monodispersed controlled release ceramic particles ofthe invention may be advantageously prepared by a sol gel process.

According to another embodiment of this invention there is providedsubstantially monodispersed controlled release ceramic particles,wherein each of said particles has an active material(s) substantiallyhomogeneously dispersed throughout the particles, wherein:

-   -   (c) the active material(s) is capable of being released from        said particles; and    -   (d) the active material(s) in said particles is substantially        protected from degradation until release of the active        material(s) from the particles.

The substantially monodispersed controlled release ceramic particles maybe functionalised or derivatised.

The rate of release of the active material(s) from said particles iscontrolled by one or more of: the nature of the active material(s),particle properties and external environment.

When the active material(s) is released from the particles into anenvironment that does not substantially affect the activity of theactive material(s), the activity of the active material(s) released fromthe particles is substantially retained.

Under usual conditions chosen for storage, transport, handling and inthe environment of use the active material(s) in said particles issubstantially protected from degradation until release of the activematerial(s) from the particles. An example of the usual conditions ofstorage, transport or handling includes storage, transport or handlingof the particles in an environment that is non corrosive to theparticles themselves. Also the usual conditions of storage, transport orhandling do not normally include exposing the particles to anenvironment where degrading materials in the environment (such as adegrading gas or liquid) can enter the particles and degrade the activematerial(s) in the particles.

The invention also provides processes for making substantiallymonodispersed controlled release ceramic particles and particles made bysuch processes.

Process 1

According to one embodiment of the invention there is provided a processof preparing controlled release ceramic particles comprising:

-   -   (a) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent;    -   (b) preparing a precursor solution by dissolving a gel        precursor, a catalyst, a condensing agent and a (or several)        soluble active material(s) in a polar solvent;    -   (c) preparing an emulsion by combining the reverse micelle        solution and the precursor solution; and    -   (d) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from said particle, by condensing the precursor in the emulsion.

Usually the particles are substantially monodispersed.

Process 2

According to another embodiment of the invention there is provided aprocess of preparing controlled release ceramic particles comprising:

-   -   (a′) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent and a hydrophilic first (or several)        active material(s);    -   (b′) preparing a precursor solution by dissolving a gel        precursor, a catalyst, a condensing agent and optionally a        soluble second (or several) active material(s) in a polar        solvent, which is immiscible with the apolar solvent used in        (a);    -   (c′) preparing an emulsion by combining the reverse micelle        solution and the precursor solution; and    -   (d′) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed.

Process 3

According to a further embodiment of the invention there is provided aprocess of preparing controlled release ceramic particles comprising:

-   -   (a″) preparing a precursor solution by mixing a gel precursor,        an (or several) active material(s) and optionally a solvent;    -   (b″) preparing a condensing solution by mixing a catalyst, a        condensing agent and optionally a solvent, said condensing        solution being substantially immiscible with said precursor        solution;    -   (c″) combining the precursor solution and the condensing        solution to form a mixture and preparing an emulsion by        spontaneously emulsifying the mixture in the absence of a        surfactant; and    -   (d″) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed. In thisembodiment the active material is one that can be dissolved in the gelprecursor or in the gel precursor together with the solvent. Inaddition, the catalyst is one that can be dissolved in the condensingagent or in the condensing agent together with the solvent. The solventreferred to in step (a″) may be the same as or different from thesolvent referred to in step (b″).

Process 4

According to yet another embodiment of the invention there is provided aprocess of preparing controlled release ceramic particles comprising:

-   -   (a′″) preparing a reverse micelle solution by mixing a        surfactant with an apolar solvent;    -   (b′″) preparing an hydrophilic solution by dissolving a        catalyst, a condensing agent and a (or several) soluble active        material(s) in a polar solvent;    -   (c′″) preparing an emulsion by combining the reverse micelle        solution and the hydrophilic solution;    -   (d′″) adding the gel precursor to the emulsion; and    -   (e′″) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed.

Product of Process 1

According to another embodiment of the invention there is providedcontrolled release ceramic particles prepared by:

-   -   (a) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent;    -   (b) preparing a precursor solution by dissolving a gel        precursor, a catalyst, a condensing agent and a (or several)        soluble active material(s) in a polar solvent;    -   (c) preparing an emulsion by combining the reverse micelle        solution and the precursor solution; and    -   (d) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed.

Product of Process 2

According to yet another embodiment of the invention there is providedcontrolled release ceramic particles prepared by:

-   -   (a′) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent and a (or several) hydrophilic first        active material(s);    -   (b′) preparing a precursor solution by dissolving a gel        precursor, a catalyst, a condensing agent and optionally a        soluble second (or several) active material(s) in a polar        solvent, which is immiscible with the apolar solvent used in        (a′);    -   (c′) preparing an emulsion by combining the reverse micelle        solution and the precursor solution; and    -   (d′) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed.

Product of Process 3

According to yet a further embodiment of the invention there is providedcontrolled release ceramic particles prepared by:

-   -   (a″) preparing a precursor solution by mixing a gel precursor,        an (or several) active material(s) and optionally a solvent;    -   (b″) preparing a condensing solution by mixing a catalyst, a        condensing agent and optionally a solvent, said condensing        solution being substantially immiscible with said precursor        solution;    -   (c″) combining the precursor solution and the condensing        solution to form a mixture and preparing an emulsion by        spontaneously emulsifying the mixture in the absence of a        surfactant; and    -   (d″) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed.

Product of Process 4

According to yet another embodiment of the invention there is providedcontrolled release ceramic particles prepared by:

-   -   (a′″) preparing a reverse micelle solution by mixing a        surfactant with an apolar solvent;    -   (b′″) preparing an hydrophilic solution by dissolving a        catalyst, a condensing agent and a (or several) soluble active        material(s) in a polar solvent;    -   (c′″) preparing an emulsion by combining the reverse micelle        solution and the hydrophilic solution;    -   (d′″) adding the gel precursor to the emulsion; and    -   (e′″) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material(s)        substantially homogeneously dispersed throughout the particle        and wherein the active material(s) is capable of being released        from each of said particles, by condensing the precursor in the        emulsion.

Usually the particles are substantially monodispersed.

The controlled release or substantially monodispersed controlled releaseceramic particles prepared by the processes of the invention may befunctionalised or derivatised.

Usually in the controlled release or substantially monodispersedcontrolled release ceramic particles prepared by the processes of theinvention the active material(s) in said particles is substantiallyprotected from degradation until release of the active material(s) fromthe particles.

The processes of the invention may include the steps of separating theceramic particles and removing solution which typically comprisessolvent and another material (such as surfactant) from the particles.The step of separating may be accomplished by known techniques such asfiltering, washing, evaporating or decanting of the solvent andsurfactant, for example.

The removal of the solvent (and surfactant) may be carried out byrinsing and/or washing of the ceramic particles with a suitable solventor combination of solvents, followed by the taking off of remainingsolvent from the particles. This may be accomplished by known techniquessuch as by absorption of the remaining solvent from the particles or byevaporating and/or drying of the ceramic particles for example.

Alternatively, the removal of the solvent (and surfactant) may becarried out after the separating by absorption of the solvent (andsurfactant) from the particles or by evaporating and/or drying of theceramic particles for example.

When solvent (and surfactant) has been removed from the ceramicparticles they are commonly referred to as controlled release ceramicxerogel particles. Controlled release silica xerogel particles areparticularly preferred.

Typically, NaCl or other suitable ionic salt (depending on the end usee.g. KI, KBr, KCl, NaBr, NaI, LiCl, LiBr, LiI, CaCl₂, MgCl₂, NH₄NO₃,NaNO₃, KNO₃, LiNO₃, etc.) is added to destabilise an emulsion after theceramic particles have been formed therein. The inventors have foundthat without the addition of an ionic salt such as NaCl the wt % ofresidual surfactant on the resultant ceramic particles is much higherthan when NaCl is used to break up the emulsion. The use of (NaCl+CHCl₃)for washing/emulsion breaking has led to <1.5 wt % residual surfactanton the resultant ceramic particles.

The purpose of removing surfactant is to avoid opsonisation(opsonisation: bonding of proteins and/or antibodies on the ceramicparticles) since this determines whether or not the particles will berejected from a subject. Preliminary testing of ceramic particles of theinvention using a Protein Assay indicates: (a) particles with highsurfactant (11.4 wt %): 40.5 μg of protein adsorbed; and (b) particleswith low surfactant (2.4 wt %: 27 μg of protein adsorbed. Further it ispreferred to wash by decantation to avoid aggregation during filtering(what is critical is the average size in solution).

One way of drying the particle, while preventing aggregation, is tofreeze-dry the particles. The present inventors have found that this canbe achieved by adding NaCl or other suitable ionic salt (e.g. NaBr, NaI,KI, KBr, KCl, LiI, LiCl, LiBr, etc.) to protect the particles duringfreeze drying and encapsulate the particles in a gangue of NaCl (FIG.17). Thus the processes of the invention may further comprise the stepsof separating the formed and aged controlled release ceramic particlesfrom the emulsion by adding an ionic salt to the emulsion whereby theparticles are dispersed in a resulting solution, and freeze drying thesolution, to form a solid in which unaggregated ceramic particles areisolated within a matrix of the ionic salt. This process may alsoinclude a step of washing the resulting solution. Typically the washingstep is carried out to substantially reduce the amount of surfactant andother materials (typically the surfactant is reduced to less than 2 wt.%, typically 0.5-2 wt. %). By ‘resulting solution’ is meant a solutionthat forms when the emulsion is broken up by the addition of the ionicsalt. Thus typically the resulting solution is an aqueous solution andthe ionic salt is NaCl. In such a case the aqueous solution is typicallywashed with an organic solvent. Examples of suitable organic solventsinclude chloroform bromoform and iodoform,—other suitable organicsolvents are known in the art.

Examples of drying processes are described in ACS Symposium 520,Polymeric delivery systems, properties and applications, I. C. Jacobsand N. S. Mason, Chapter 1, Polymer Delivery Systems Concepts, pp. 1-17,1993, the contents of which are incorporated herein by cross reference.

Another embodiment of the invention provides a composition comprisingcontrolled release ceramic particles according to the invention togetherwith an acceptable carrier, diluent, excipient and/or adjuvant.

A further embodiment of the invention provides a method of treating alocus comprising applying controlled release ceramic particles of theinvention or a composition according to the invention to the locus in anamount effective to treat the locus.

Another embodiment of the invention provides a method of treating anobject comprising administering to the object controlled release ceramicparticles of the invention or a composition according to the inventionto the object in an amount effective to treat the object.

Yet a further embodiment of the invention provides a method of treatinga subject comprising administering to the subject controlled releaseceramic particles of the invention or a composition according to theinvention to the subject in an amount effective to treat the subject.

The ceramic microparticles of the invention are prepared by a sol-gelbased process in which partly hydrolysed oxides of suitable metals(including transition metals, silicon, etc.) are prepared in thepresence of an active material by hydrolysis of the gel precursorfollowed by condensation (alternatively referred to aspolycondensation). The gel precursor may be a metal oxide gel precursorincluding silicon oxide gel precursor, transition metal oxide precursor,etc. The identity of the gel precursor chosen that is, whether a siliconoxide gel precursor or a particular metal oxide gel precursor chosen foruse in a process of the invention, will depend on the intended use ofthe ceramic particles and, in particular, the suitability of the finalproduct resulting from the condensation of the gel precursor for theintended use of the ceramic particles. The gel precursor is typically asilica-based gel precursor, an alumina-based gel precursor, a titaniumdioxide-based gel precursor, an iron oxide based gel precursor, azirconium dioxide-based gel precursor or any combination thereof. Afunctionalised, derivatised or partially hydrolysed gel precursor may beused.

For silica there is a long list of potential silicon precursors whichfor convenience can be divided into 4 categories, the silicates (siliconacetate, silicic acid or salts thereof) the silsequioxanes andpoly-silsequioxanes, the silicon alkoxides (from silicon methoxide (C₁)to silicon octadecyloxide (C₁₈)), and functionalised alkoxides forORMOCER production (such as ethyltrimethoxysilane,aminopropyltriethoxysilane, vinyltrimethoxysilane,diethyldiethoxysilane, diphenyldiethoxysilane, etc). Further specificexamples of silica-based gel precursors include tetramethoxysilane(TMOS), tetraethoxysilane (TEOS), tetrabutoxysilane (TBOS),tetrapropoxysilane (TPOS), polydiethoxysilane, methyltrimethoxysilane,methyltriethoxysilane, ethyltriethoxysilane, octylpolysilsesquioxane andhexylpolysilsesquioxane-.

Examples of alumina-based gel precursors include aluminium ethoxide,aluminium n- or iso-propoxide, aluminium n- or sec- or tert-butoxide.The alkoxide can also be modified using carboxylic acids (acetic,methacrylic, 2-ethylhexanoic, etc) or beta di-ketones such asacetylacetone, ethyl-acetylacetone, benzoylacetone, or other complexingagent. Upon hydrolysis, ORMOCER (Organically Modified Ceramics)particles are typically formed. As for silica they can be useful inpreventing the interaction of the drug with the ceramic matrix.

Examples of titanium or zirconium gel precursors include the alkoxides(ethoxide, propoxide, butoxide), the metal salts (chloride, oxychloride,sulfate, nitrate) and the acid and beta diketone complexes.

The silica gel precursor or the metal oxide gel precursor may includefrom one to four alkoxide groups each having from 1 or more oxygenatoms, and from 1 to 18 carbon atoms, more typically from 1 to 5 carbonatoms. The alkoxide groups may be replaced by one or more suitablemodifying groups or functionalised or derivatised by one or moresuitable derivatizing groups (see K. Tsuru et al., J. Material Sci.Mater. Medicine, 1997, 8, the contents of which are incorporated hereinby cross-reference).

Typically, the silica gel precursor is a silicon alkoxide or a siliconalkyl alkoxide.

Particular examples of suitable silicon alkoxide precursors include suchas methoxide, ethoxide, iso-propoxide, butoxide and pentyl oxide.Particular examples of suitable silicon or metal alkyl (or phenyl)alkoxide precursors include methyl trimethoxysilane,di-methyldimethoxysilane, ethyltriethoxysilane, diethyldiethoxysilane,triethyl-methoxysilane, phenyltriethoxysilane, diphenyldiethoxysilane,vinyltriethoxysilane, etc. Alternatively, the silica gel precursor maybe a silicon carboxylate. For example, an acetate, tartrate, oxalate,lactate, propylate, formate, or citrate. Examples of other functionalgroups attached to silica gel precursors include esters, alkylamines andamides.

Typically, the metal oxide gel precursor is a metal alkoxide which maybe derivatised or functionalised. Typically the transition metal oxidegel precursor is a transition metal alkoxide and the lanthanide metaloxide gel precursor is a lanthanide metal alkoxide. Examples of suitablemetal oxide precursors include alkoxides such as methoxide, ethoxide,iso-propoxide, butyloxide and pentyl oxide. Alternatively, metal oxidegel precursor may be a metal carboxylate or a metal beta-diketonate, forexample, an acetate, tartrate, oxalate, lactate, propylate, formate,citrate, or acetylacetonate. Examples of other functional groupsattached to metal oxide precursors include esters, alkylamines andamides. More than one type of metal ion or lanthanide ion may be present(e.g. silicon titanium oxide, see example 23).

Sol-gel processing is based on the hydrolysis and condensation ofappropriate precursors, which, in most cases, involves the reaction ofan alkoxide (either modified or unmodified) with water (i.e. thehydrolysis step). Water is thus typically used as the condensing agent.Thus a typical reaction scheme may be represented as shown in FIG. 16.

Appropriate condensing agents other than water may be used where anon-aqueous sol-gel route is used via Process 3. Examples of severalnon-aqueous methods that are envisaged via process 3 are as follows:

-   -   Hydroxylation in non-aqueous systems.    -   Aprotic condensation reactions.    -   Ester elimination reaction by condensing alkoxides with        carboxylate functional groups.    -   Ether elimination by condensing alkoxide with alkoxide, thus        liberating dialkyl ether.    -   Oxolation not involving hydrolysis, via reaction of alkoxide        with hydrogen halide or ketone (in the case of basic alkoxide        such as Zn alkoxide).    -   Reactions of organic oxygen donors, such as dialkyl ether or        dialkyl ketone, with metal halides.

The latter two reactions may be unsuitable for many applications sincethey involve the use of metal halides, which in turn generatechlorinated compounds which are highly toxic and could be difficult toremove by washing.

A suitable surfactant is a straight chain hydrocarbon having ahydrophilic head group such as, for example, a sorbitan, polyether,polyoxyethylene, sulfosuccinate, phosphate, carboxylate, sulfate, aminoor acetylacetonate and a hydrophobic tail group. The tail group may befor example, straight or branched chain hydrocarbon which can have fromabout 8 to 24 carbon atoms, preferably from about 12 to 18 carbon atoms.It may contain aromatic moieties such as for example iso-octylphenyl.

(A) The first way to classify surfactants is according to their HLB's(Hydrophile Lypophile Balance, see page 48 of the M. F. Cox article inDetergents and Cleaners: A Handbook for Cleaners', Hanser/GardnerPublications, Inc., Ohio, USA. 1994, pp. 43-90, the contents of which(pp. 43-90) are incorporated by cross reference.

-   -   a) surfactants with HLB>10 are typically used for oil in water        emulsions.    -   b) surfactants with HLB<10 are typically used for water in oil        emulsions. A mixture of surfactants usually forms a more stable        emulsion than either surfactant alone.

(B) Surfactants can also be classified according to their charge, i.e.cationic, anionic, or non ionic, although such a classification is notas relevant to the present invention. In general non-ionic surfactantare typically preferred, since they can be more easily removed bywashing. The ionic type tends to complex the surfaces of oxide particlesbut can be often removed by changing the pH of the surface (i.e. washingwith acid or base).

More relevant is the empirical classification by size. An extensivereview of the literature on ceramic particle synthesis in emulsionsuggests that:

-   -   1) Sorbitan esters (e.g. sorbitan monooleate, monopalmitate,        monostearate), sold under the trade mark Span, may be used to        provide particles >1 μm.    -   2) Alkylarylpolyether also called alkyl phenol ethoxylates,        which are sold under the trade name Triton, may be used to        provide particles smaller than 0.5 μm.    -   3) Alcohol ethoxylates are also used to synthesise nanoparticles        in water-in-oil emulsions. They are sold under the trade names        Brij (polyoxyethylene alkyl ether) and Tween (polyoxyethylene        sorbitan alkylate). Typically such surfactants may be used to        synthesise particles less than 1 μm.    -   4) AOT or aerosol OT or sodium bis(2-ethylhexyl)sulfosuccinate        is an anionic surfactant used for synthesising particles from 5        nm to 1 μm.

There are also other surfactants which may be used such asblock-copolymers.

The choice of the nature of the surfactant/solvent determines theparticle size range.

The particle size increases with H (water/metal) and decreases with S(surfactant/metal):

-   -   Particle size increases with R (water/surfactant)    -   Droplet sizes increases with R    -   More water=larger droplets=larger micro-reactor

The control of the particle size range is achieved by choice of thesurfactant and adjustment of R (the particle size can be tailored in therange of 50-500 nm by changing R (water/surfactant) and/orsurfactant/solvent. The catalyst may be an acidic or basic catalyst andis generally chosen so as to be compatible with the active material i.e.it is chosen so as not to deactivate the active material. Examples ofacidic catalysts include mineral acids such as sulfuric acid, phosphoricacid, HCl and HNO₃. Organic acids such as acetic acid, tartaric acid,succinic acid and salicylic acid may be used. Examples of basiccatalysts include NaOH, KOH, ammonium hydroxide, Ca(OH)₂, etc.Essentially the catalyst catalyses the reaction between the gelprecursor and the condensing agent.

The pH and ionic strength of the solution in which the hydrolysis,micelle formation and aging occur can vary over a wide range dependingon the nature of the active material. However, the rate of hydrolysis,the rate of aging or rate of polycondensation (also referred to hereinas condensation) is affected by these parameters and can vary accordingto the metal oxide precursor. Generally, the pH used in the agingprocess can range from about 0-14, and is typically between about 1-11.When an acidic catalyst is used the pH range is typically 1-6.5, andeven more typically 1-4.5. When a basic catalyst is used the pH range istypically 7-14, more typically 7-11. The pH at which thepolycondensation (or condensation) is carried out is normally chosen soas to be at a value or within a certain pH range that does notsubstantially affect the activity of the active materials (which willdepend on the nature of the active materials or the stability of thesurfactant). One of ordinary skill in the art can determine optimal pHsand ionic strengths for particular gel precursors/active materialcombinations using the methods described herein, for example. Otherranges of pH in which the hydrolysis, micelle formation and aging mayoccur when an acidic catalyst is used are 1-7, 1-6, 1-5, 1-4, 1-3, 1-2,2-7, 2-6, 2-5, 2-4, 2-3, 3-7, 3-6, 3-5, 3-4, 4-7, 4-6, 4-5, 5-7, 5-6 or6-7. Specific pH's in which the hydrolysis, micelle formation and agingmay occur when an acidic catalyst is used include 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 5.5, 6, 6.5 and 7. Other ranges of pH in which thehydrolysis, micelle formation and aging may occur when a basic catalystis used are 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 7-8, 8-14, 8-13, 8-12,8-11, 8-10, 8-8, 9-14, 9-13, 9-12, 9-11, 9-10, 10-14, 11-13 or 11-12.Specific pH's in which the hydrolysis, micelle formation and aging mayoccur when a basic catalyst is used include 7.5, 8, 8.5, 9, 9.5, 10,10.5, 11, 11.5, 12, 12.5, 13 and 13.5.

The maximum processing and aging temperatures are typically in the range0-100° C. but more typically around room temperature, 20-30° C. Themaximum temperatures of the processing and aging depends on thevolatility of the solvent used. Typically the processing of theinvention is carried out at a temperature in the range 1° C.-100° C., 0°C.-75-C., 0° C.-50°-C., 1° C.-50° C., 10° C.-100° C., 1° C.-75° C., moretypically 0° C.-40° C., 1° C.-40° C., 5° C.-40° C., 10° C.-40° C., 15°C.-40° C., 20° C.-40° C., 25° C.-40° C., 30° C.-40° C., or 35° C.-40° C.Typically the aging is carried out at a temperature in the range 0°C.-100° C., more typically in the range 0° C.-75° C., 0° C.-50° C., 0°C.-40° C., 5° C.-40° C., 10° C.-40° C., 15° C.-40° C., 20° C.-40° C.,25° C.-40° C., 30° C.-40° C. or 35° C.-40° C.

The aging time is typically between 0-30 days but more typically from 30min to 12 hr and even more typically of 1 hr. Typically the aging iscarried out for a period in the range 30 minutes to 5 weeks, moretypically 0.5 hours-4 weeks, 0.75 hours-4 weeks, 1 hour-4 weeks, 0.5hours-3 weeks, 0.75 hours-3 weeks, 1 hour-3 weeks, 0.5 hours-2 weeks,0.75 hours-2 weeks, 1 hour-2 weeks, 0.5 hours-1 week, 0.75 hours-1 week,1 hour-1 week, 0.5 hours-5 days, 0.75 hours-5 days, 1 hour-5 days, 0.5hours-3 days, 0.75 hours-3 days, 1 hour-3 days, 0.5 hours-2 days, 0.75hours-2 days, 1 hour-2 days, 0.5 hours-1 day, 0.75 hours-1 day, 1 hour-1day, 0.5 hours-20 hours, 0.75 hours-20 hours, 1 hour-20 hours, 1 hour-15hours, 2 hours-15 hours, 3 hour-15 hours, 1 hour-10 hours, 2 hours-10hours, 3 hours-10 hours, 1 hour-5 hours, 2 hours-5 hours, or 3 hours-5hours.

The drying temperature can be from −196° C. (in liquid N₂ for freezedrying) to 300° C. for supercritical drying, but is more typically from20° C. to 80° C. The maximum temperature is dictated by the thermalstability of the active ingredient(s) encapsulated in the particles.Typically drying is carried out at a temperature in the range 10° C.-50°C., more typically 12° C.-40° C., 15° C.-40° C., 17° C.-40° C., 19°C.-40° C., 20° C.-40° C., 25° C.-40° C., 30° C.-40° C. or 35° C.-40° C.

The drying time is typically between 30 minutes-30 days but moretypically from 1 day to 1 week and even more typically 0.25, 0.5, 0.75,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 days.

The particle size can be tailored typically between 1 nm and 100 μm butmore typically between 10 nm and 50 μm. The particle size of thecontrolled release ceramic particles may be in the ranges of 1 nm-100μm, 1 nm-90 μm, 1 nm-80 μm, 1 nm-70 μm, 1 nm-60 μm, 1 nm-50 μm, 1 nm-40μm, 1 nm-30 μm, 1 nm-20 μm, 1 nm-10 μm, 1 nm-7.51 μm, 1 nm-5 μm, 1nm-2.5 μm, 1 nm-1.5 μm, 1 nm-1 μm, 1 nm-0.5 μm, 1 nm-0.1 μm, 1 nm-100μm, 10 nm-50 μm, 10 nm-20 μm, 100 nm-100 μm, 100 nm-50 μm, 100 nm-10 μm,100 nm-10 μm, 500 nm-100 μm, 500 nm-50 μm, 500 nm-10 μm, 500 nm-1 μm,750 nm-100 μm, 750 nm-50 μm, 750 nm-10 μm, 750 nm-1 μm, 1-100 μm, 1-50μm, 1-25 μm, 1-10 μm, 10-100 μm, 10-75 μm, 10-65 μm, 10-55 μm, 10-50 μm,10-45 μm, 10-35 μm, 10-25 μm, 10-15 μm, 1-10 μm, 1-7.5 μm, 1-6.5 μm,1-5.5 μm, 1-4.5 μm, 1-3.5 μm, 1-2.5 μm, 1-1.5 μm.

The elemental composition of the microparticles may affect theircontrolled release properties. Thus additives which result in elementssuch as C, Fe, Ti, N, Cl, Mg, P, Ca, K and/or Na, or other suitableelements being included in the ceramic particles may be added prior toany substantial polycondensation reaction occurring in the process ofthe invention to alter the composition of the particles as desired.Other examples of additives may be found in D. Avnir et al., Chemistryof Materials, 6, 1605-1614, 1994, the contents of which are incorporatedherein by cross reference.

Other parameters which may be used to control the properties of theceramic particles include gel precursor:water ratio, gelprecursor:miscible solvent ratio, water:miscible solvent ratio, size ofthe ceramic particles, chemical composition of the ceramic particles,aging conditions and condensation rate.

The controlled release rate of the active material from the ceramicparticles may be adjusted to the desired rate by appropriately adjustingthe various parameters and additives mentioned throughout thisspecification.

The nature of the active materials in the compositions and methods ofthe invention will depend on the intended use. An effective amount ofactive materials is added to the appropriate mixture prior topolycondensation taking place to any significant extent.

More than one active material may be incorporated in the ceramicparticles of the invention (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or moreactive materials).

Active materials may be any biological active material such as organic,inorganic or organo metallic pharmaceutically active compounds, aminoacids, polyamino acids, nucleic acids, polypeptides, proteins forexample, hormones, enzymes, and globulins, and vitamins or mixturesthereof. Active materials which have been incorporated into liposomesand which have been described in G. Gregoriadis editor, ‘Liposomes’,Drug Carriers in Biology and Medicine, pp. 287-341, Academic Press, NewYork, 1979, the contents of which are incorporated herein by crossreference, may also be incorporated in the ceramic particles of theinvention. Examples of the classes of pharmaceuticals from which apharmaceutically active compound may be selected and incorporated in aceramic particle of the invention via a process of the invention includeantibiotics, antibacterials, analgesics, anaethetics, muscle relaxants,anti-inflammatories, antidepressants, anticoagulants, antipsychotics,antihypertensives, antiasthmatics, anticonvulsants, antivirals andantidiabetics. Examples of pharmaceutically active materials aredisclosed in U.S. Pat. Nos. 4,952,402, 4,474,752 and 5,952,004 thecontents of which are incorporated herein by cross reference. The activematerial may be a radiopharmaceutical (see for example U.S. Pat. Nos.5,762,907, 5,550,160, and 5,496,533, the contents of which areincorporated herein by cross reference for a non comprehensive listexamples of radiopharmaceuticals) including a radiolabelled protein (seefor example U.S. Pat. No. 5,736,120 the contents of which areincorporated herein by cross reference for a non comprehensive listexamples of radiolabelled proteins) and a radiolabelled carbohydrate orthe active material may be a radiotracer. Typically the biologicallyactive material is suitable for human use or veterinary use. Otherclasses of active materials include insecticides, fungicides,herbicides, miticides, nematicides, pesticides, antimicrobials,perfumes, fragrances, colorants or mixtures thereof.

The polar solvent used in the process of the invention may be water or apolar organic solvent. An organic solvent is typically used in someprocesses of the invention in addition to water used in the hydrolysis.Organic solvents that are miscible with water and are polar or solventsthat can be partly dissolved in water can be used such as n-, sec- ortert-C₁-C₆ alkanols such as for example, methanol, ethanol, propanol,isopropanol, n-butanol, sec butanol or tert-butanol as well as ketonessuch as acetone, and methyl ethyl ketone, amines such as dipropylamine,esters such as methylacetate, water soluble ethers, polyhydric alcoholssuch as ethylene glycol or di- or tri-ethylene glycol. Examples ofnon-polar solvents that may be used in the process of the inventioninclude alkanes (from hexane (C6) to dodecane (C12) and cycloalkanessuch as cyclohexane), aromatic compounds (e.g. toluene, benzene) andcommercial mixtures such as kerosene. In one process of the invention,for example, a metal gel precursor such as metal alkoxide is dissolvedin a water miscible polar organic solvent such as, for example, ethanol.Water is added to the metal alkoxide solution (or water may be includedin the organic solvent in the first instance). The active material isadded to obtain a solution or dispersion. The active material may beadded as a solution in the organic solvent or water or mixture of theorganic solvent and water. A base (e.g. NaOH, KOH, NH₃, etc.) or an acid(HCl, HNO₃, acetic acid, formic acid, etc.) is added as catalyst(depending on the nature of the active material) so as to not adverselysubstantially affect the activity of the active material. The mixture ismixed at room temperature. The mixture is then added to a reversemicelle solution with stirring to form an emulsion and allowed to age(under stirring) so as to form substantially monodispersed ceramicparticles. The substantially monodispersed particles are then typicallyseparated from the combined mixture by standard techniques such asfiltration and washing. Typically the surfactant is removed by washingwith a solvent in which the active material is substantially insolubleor very slowly soluble. The ceramic particles are then typically driedand during the drying process any excess solvent is removed from theceramic particles.

Other molecules may be attached to or coupled to or coated on theceramic particles of the invention if desired. For example a targetingmolecule such as an antibody or receptor molecule may be attached to orcoupled to or coated on the ceramic particles of the invention. Examplesof active targeting molecules are described in F. Carli, La Chimica &L'Industria, 404-498, 1993, L. Brannon-Peppas et al., Polymer News, 2,316-318, and A. V. Kabanov and V. Y. Lalkhov, J. Controlled Release, 28,15-35 (1994), the contents of all of which are incorporated herein bycross reference.

Applications of the invention include the delivery and controlledrelease of pharmaceuticals, hormones, proteins, etc. Controlled releaseof fertilisers, pesticides, herbicides, insecticides, biocides,perfumes, etc are also within the scope of the invention.

Where the controlled release ceramic particles are used in the form of acomposition comprising controlled release ceramic particles, a carrier,diluent, excipient and/or adjuvant appropriate to the intended use isused. Thus where the active material is (a) a fertiliser—anagriculturally acceptable carrier, diluent, excipient and/or adjuvant isused; (b) a pesticide—a pesticidally acceptable carrier, diluent,excipient and/or adjuvant is used; (c) a herbicide—a herbicidallyacceptable carrier, diluent, excipient and/or adjuvant is used; (d) aninsecticide—an insecticidally acceptable carrier, diluent, excipientand/or adjuvant is used; (e) a biocide—a biocidally acceptable carrier,diluent, excipient and/or adjuvant is used; (f) a perfume—a carrier ordiluent acceptable for a perfume is used; (g) a pharmaceutical—a carrieror diluent or adjuvant acceptable for pharmaceutical use; (h) aveterinary product—a carrier or diluent or adjuvant acceptable forveterinary use etc.

Advantageously in the method of the invention concerned with treating asubject the subject is a mammal or vertebrate. The mammal or vertebrateis typically selected from human, bovine, canine, caprine, ovine,leporine, equine, or feline vertebrate. Advantageously the vertebrate isa human, domestic fowl, bird, bovine, canine, ovine, leporine, equine,caprine, or feline vertebrate. Alternatively, the subject may be a fish,insect, or other suitable subject.

The composition may be a veterinarily acceptable composition or apharmaceutically acceptable composition.

Typically, the mammal is a human and the composition is apharmaceutically acceptable composition which comprises controlledrelease ceramic particles according to the invention and at least onepharmaceutically acceptable carrier, adjuvant and/or excipient. Wherethe animal is a mammal, the composition is generally a veterinarilyacceptable composition which includes at least one veterinarilyacceptable carrier, adjuvant and/or excipient together with controlledrelease ceramic particles of the invention. For parenteraladministration, the controlled release ceramic particles of theinvention of suitable size for the intended use may be prepared insterile aqueous or oleaginous solution or suspension. Suitable non-toxicparenterally acceptable diluents or solvents include isotonic saltsolution, water, ethanol, Ringer's solution, 1,3-butanediol, propyleneglycol or polyethylene glycols in mixtures with water. Aqueous solutionsor suspensions may further include one or more buffering agents.Examples of buffering agents include sodium citrate, sodium acetate,sodium borate or sodium tartrate.

Depending on the intended purpose, the dosage form of the compositionwill comprise from 0.01% to 99% by weight of the ceramic particles ofthe invention. Usually, dosage forms according to the invention willcomprise from 0.01% to about 20%, more typically 0.05% to 15% and evenmore typically 0.1% to 5% by weight of the ceramic particles of theinvention.

Compositions of the invention may be prepared by means known in the artfor the preparation of compositions (such as in the art of preparingveterinary and pharmaceutical compositions) including blending,homogenising, suspending, emulsifying, dispersing and where appropriate,mixing of the ceramic particles together with the selected excipient(s),carrier(s), adjuvant(s) and/or diluent(s). However, the process ofcombining the particles of the invention with excipient(s), carrier(s),adjuvant(s) and/or diluent(s) should not be such as to destroy orsubstantially damage the ceramic particles.

In methods of administration the invention, the ceramic particles orcompositions may be administered orally, topically, parenterally, e.g.by injection and by intra-arterial infusion, rectally or by inhalationspray or by way of a dermal patch.

A suitable treatment may comprise the application or administration of asingle dose or multiple doses. If more than one type of ceramic particleis involved in the treatment each type of ceramic particle may beadministered at the same time or at different times (includingsequentially).

As indicated the administered dosage of the ceramic particles will varyand depends on several factors, such as the condition, age and size ofthe patient as well as the nature of the condition and the activematerials and the effectiveness of the active materials. A typicaldosage range may be from 0.0001 mg to 200 mg of active materials per kgin the case where an antimicrobial is the active material. Usually, thedose of an antimicrobial is in the range of from 0.001 mg to 10 mg perkg of body weight. For more specific details concerning various types ofantimicrobials including sulfonamides, antibiotics, antifungals,antiprotozoans as well as dosage regimes see, for example, “Pharmacologyand Drug Information for Nurses” Society of Hospital Pharmacists ofAustralia, W. B. Saunders, Harcourt Brace Jovanovich, Publishers, 3rdEdition, V. E. Richardson (edit.) Sydney, 1989, “Antibiotics: TheComprehensive Guide”, I. K. M. Morton, J. Halliday, J. M. Hall and A.Fox, Consultants, Bloomsbury Publishing limited, London 1990,Remington's Pharmaceutical Sciences”, A. R. Gennaro (edit.) MackPublishing Company, Pennsylvania, 1990, Kirk-Othmer “ConciseEncyclopedia of Chemical Technology” John Wiley & Sons, Inc., New York,N.Y., USA 1985, and “The Australian Guide To Prescription Drugs”, M.Goyen, The Watermark Press, Sydney (1991) the contents of all of whichare incorporated herein by cross reference.

Suspensions for oral administration may further comprise additives asrequired such as dispersing agents, suspending agents, and the like.

Solid forms for oral administration may contain pharmaceutically orveterinarily acceptable sweeteners, binders, disintegrating agents,flavourings, diluents, coating agents, preservatives, lubricants and/ortime delay agents (chosen as to not substantially affect the controlledrelease mechanism). Liquid forms for oral administration may contain, inaddition to the above agents, a liquid carrier.

Emulsions for oral administration may further comprise one or moreemulsifying agents. For oral administration, the pharmaceutical orveterinary composition may be in the form of tablets, lozenges, pills,troches, capsules, elixirs, powders, including granules, suspensions,emulsions, syrups and tinctures. Slow-release, or delayed-release, formsmay also be prepared, for example in the form of coated particles ormulti-layer tablets or slow release capsules of ceramic particles.

Examples of dosage forms are as follows:

-   -   1 Tablet: Ceramic Particles Having Antimicrobial(s)—0.01 to 25        mg, generally 0.1 to 15 mg; Starch—5 to 25 mg; Lactose—80 to 280        mg; Gelatin—0 to 10 mg; and Magnesium stearate—0 to 10 mg.    -   2. Topical Cream: Ceramic Particles Having Antimicrobial(s)        0.1-15% (w/w), demineralized or distilled water—0.1-12% (w/w),        surfactants 1-12% (w/w), thickening agents—0.1-3% (w/w),        parabens 0.1-2% (w/w), vegetable oil 5-22% (w/w), mineral oil        0-12% (w/w), stearic acid 0-12% (w/w), and lanolin 0-12% (w/w).

The invention includes in particular compositions which are used fortopical application which may be a cream, ointment, paste, solution,emulsion, lotion, milk, jelly, gel, stick, roll-on or smooth-on, whereinthe ceramic particles comprises up to about 90%, more typically 10%, byweight of the composition, even more typically from about 0.1% to about4% by weight, for example 3.5% by weight and the compositions includetopically suitable carriers, diluents, excipients, adjuvants and otheradditives.

For topical administration, the pharmaceutical or veterinary compositionmay be in the form of a cream, ointment, gel, jelly, tincture,suspension or emulsion. The pharmaceutical composition may containpharmaceutically acceptable binders, diluents, disintegrating agents,preservatives, lubricants, dispersing agents, suspending agents and/oremulsifying agents as exemplified above. The veterinary composition maycontain veterinarily acceptable binders, diluents, disintegratingagents, preservatives, lubricants, dispersing agents, suspending agentsand/or emulsifying agents as exemplified above. Other additivestypically include bacteriocides, buffering agents, thickening agents andemollients.

Additionally, it will be understood that the topical compositions of theinvention may include suitable colouring agents and/or perfumes wellknown in the art. Typical examples of suitable perfuming agents areprovided in S. Arctander, “Perfume and Flavor Chemicals”, Montclair,N.J., 1969.

It will be appreciated that the examples referred to above areillustrative only and other suitable carriers, diluents, excipients andadjuvants known to the art may be employed without departing from thespirit of the invention.

This invention involves a generic approach to the synthesis of sol-gelsilica (and alumina, zirconia, or titania) matrices for controlling therelease of bioactive materials over periods ranging from hours tomonths. Biological materials or other active materials are incorporatedinto the matrix during gelation at, or near, ambient temperature.Interactions between the matrix and the encapsulated species can beminimised by functionalisation of the surface using organically modifiedsol-gel precursors, such as methyltrimethoxysilane, vinyl trimethoxysilane, (3-glycidyloxypropyl)trimethoxysilane, etc:

The particles are produced in the form of substantially monodispersedcontrolled release ceramic particles, which are typically spherical,with an average size which can be varied typically in the range from 10nm to 50 μm.

The diffusion rate of the encapsulated species may be varied bycontrolling the matrix structure (porosity, pore size and tortuosity)and particle size. Generally, the diffusion follows the law:[C₁]/[C₀]=Dt^(−1/α) where C₀ is the concentration of active materialwhich has diffused out of the ceramic particles after time t=0 sec,C_(t) is the concentration of active material which has diffused out ofthe ceramic particles after time t, D is the experimental diffusioncoefficient of the active material and α is a parameter dependent on theproperties of the particles affecting diffusion of the active material(e.g. pore size or diameter φp, tortuosity and size or effectivediameter, Φ_(m), of the active material). Typically, when φp/φ_(m)>10then α≈2 (i.e. Fick's 1^(st) law), when 10>φp/φ_(m)>2 then α≈d_(s)(where d_(s) is the surface fractal dimension), and when 2>φp/φ_(m) thevalue of α has to be determined experimentally.

The release rate is a function of the diffusion of the encapsulatedspecies in the matrix and matrix dissolution.

The external surface of the sol-gel oxide particles can be easilyfunctionalised to promote bioadhesion, or to modify in-vivobiodistribution of the particles.

The invention provides a generic approach to the controlled delivery ofa multitude of drugs and other active materials. The same matrix andparticle sizes can be used with a wide range of different drugs andactive materials.

The invention provides the possibility of producing different particlesizes for different applications with the same generic sol-gelchemistry.

The choice of particle size is determined by the specific application,rather than the drug or active material.

Easy functionalisation of the microspheres surface, to provide activetargeting of the drug molecule or other active molecule.

-   -   Silica is bio-degradable and bio-compatible.    -   Relative mechanical stability of the matrix. No explosions or        burst effects are observed as can occur with liposomes or        reservoir systems.    -   Examples of Potential Applications    -   Controlled delivery of:    -   Pharmaceuticals for human health care application—    -   subcutaneous delivery (microparticles)    -   intra-muscular delivery (microparticles)    -   intranasal and inhalation delivery system (microparticles)    -   vaginal applications (microparticles)    -   rectal applications (microparticles)    -   intravenous delivery (nanoparticles)    -   ocular delivery (nanoparticles)    -   passive organ targeting by size (liver, lungs)    -   transdermal patch (coating and microparticles) where:        microparticles: 1 to 50 μm nanoparticles: 10 to 500 nm.    -   Drugs for veterinarian applications (see above);    -   Controlled release of:    -   Fertilisers;    -   Pesticides;    -   Herbicides;    -   Insecticides;    -   Biocides;    -   Perfumes

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1-1: Influence of D (D=molar ratio of alcohol to silicon alkoxide)on the release from gels synthesised with W=8 (W=molar ratio of water tosilicon alkoxide)

FIG. 1-2: Influence of W on the release from gels synthesised withoutmethanol (D=0)

FIG. 2-1: Influence of the pH on the release for gels synthesised withW=4 and D=4. Acid region

FIG. 2-2: Influence of the pH on the release for gels synthesised withW=4 and D=4. Basic region.

FIG. 3: Influence of MTMS (MTMS=methyltrimethoxysilane) substitution onrelease rate.

FIG. 4: Influence of the syneresis time on the release of Orange II(Orange II=(4-(2-hydroxy-naphthylazo) benzene sulfonic acid, sodiumsalt).

FIG. 5: Influence of the drying on the release from a gel synthesisedwith W=4 and D=0.

FIG. 6: Block diagram showing a preferred process 1 of the invention.

FIG. 7: Influence of the temperature of the release media on the releaserate.

FIG. 8: Comparison of the release of gels containing Orange II andMethyl violet.

FIG. 9: Microspheres synthesised using a) heptane, b) octane c) dodecaneand d) cyclohexane.

FIG. 10: Influence of the surfactant chain length on the size of themicrospheres synthesised in dodecane. a) sorbitan monooleate and b)sorbitan monolaurate.

FIG. 11: SEM micrograph of nanospheres synthesised using anAOT/cyclohexane emulsion (AOT=Aerosol OT or sodium bis(2-ethylhexyl)sulfosuccinate).

FIG. 12-1: Influence of the sol-gel chemistry on the release rate ofmicrospheres.

FIG. 12-2: SEM micrographs of the surface of microspheres synthesisedfrom sol-gel solutions at pH=2 and pH=9.

FIG. 13: Influence of the drying temperature of microspheres on theirrelease kinetics.

FIG. 14: TEM micrograph showing the precipitation of platinum colloidsin the aged TMOS derived gel containing cis-platin.

FIG. 15-1: Influence of the incorporation of MTMS on the release rate ofcycloheximide.

FIG. 15-2: Influence of the incorporation of MTMS on the release rate ofcis-platin.

FIG. 16: Equations of hydrolysis and condensation.

FIG. 17-1: Freeze dried nanoparticles encapsulated in a gangue of sodiumchloride.

FIG. 17-2 Redispersed nanoparticles in water-particles with an averageparticle size around 200 nm.

FIG. 17-3 Redispersed nanoparticles in water-graph showing a narrow sizedistribution.

FIG. 18-1 A TEM micrograph dried Cu-doped particles indicating thattheir diameter is ca. 50 nm.

FIG. 18-2 Photon correlation spectroscopy of a suspension of theparticles of FIG. 18-1 confirming that the average particle size insolution was 51 nm.

FIG. 19 SEM of ceramic particles indicating that an increase in S leadsto a corresponding decrease in the particle size.

FIG. 20 Graph showing particle size distributions of nanoparticles.

FIG. 21 SEM micrograph of particles prepared by process 3.

FIG. 22 SEM photograph of TiO₂/SiO₂ mixed oxide particles doped withOrange II prepared by process 1.

FIG. 23: Block diagram showing a preferred process 4 of the invention.

FIG. 24: Block diagram showing a preferred washing procedure in relationto process 4 of the invention.

BEST MODE AND OTHER MODES OF CARRYING OUT THE INVENTION

FIG. 6 illustrates in block diagram form a preferred process ofpreparing substantially monodispersed controlled release ceramicparticles, typically microspheres. The preferred process is described indetail below.

Gel Microsphere Preparation (Mainly Applicable to Process 1)

A sol-gel solution (solution A) is synthesised by adding a solution ofsilicon alkoxide (or organically modified silicon alkoxide) in alcoholto a solution of water in alcohol in which the bio-active molecules havebeen dissolved. The resulting mixture is set aside to start thecondensation of the alkoxides into the corresponding metal oxide (i.e.silica).

A solution (solution B) is prepared by mixing a surfactant (eg. sorbitanmono-oleate, sorbitan mono-palmitate, AOT) with a non polar solvent.Solution B can be considered as a suspension of reverse micelles made bythe surfactant.

Upon addition of A to B, the hydrophilic solution A migrates to theinside of the micelles forming an emulsion. The condensation reactionswhich have started upon addition of the water are accelerated upon suchconfinement. This leads to mass gelation of the liquid droplets and theproduction of substantially monodispersed controlled release poroussilica microspheres containing the bioactive molecules trapped insidethe pores. The particles are then filtered, washed to remove thesurfactant and dried.

Controlled Release (Applicable to All Processes)

The internal matrix structure (especially pore size and tortuosity),particle size, overall active ingredient loading and/or matrixsolubility determines the active ingredient delivery rates in controlledrelease systems. A significant limitation of polymeric controlledrelease matrices is that they can only exploit one, or at most two, ofthese features, and any changes in the active ingredient(s) necessitatesa significant reformulation of the matrix system. In contrast, thepresent invention enables all of these features to be exploited usingthe same underlying chemistry:

The internal microstructure of the spheres can be precisely tailored (asin bulk gels) by varying such sol-gel processing parameters as thewater-to-alkoxide ratio (W), pH, alcohol-to-alkoxide ratio, alkoxideconcentration, aging (i.e. syneresis), drying time and temperature.Hence, the active ingredient(s) release rate is controlled by adaptingthe structure of the internal pore network (i.e. volume, diameter andtortuosity) to the physico-chemical properties of the active ingredientmolecule.

The diameter of the ceramic particle is controlled by the size of theemulsion droplets, which is determined by the hydrophile-lipophilebalance between the surfactant, aqueous phase and the non-polar solvent.Constant (zero-order) release rate can be obtained by fully entrappingthe active ingredient(s) inside the silica matrix. The particles areproduced in the form of substantially monodispersed spherical particleswith a size which can be readily varied. The release rate of the activematerial is dependent on the size of the ceramic particle.

The overall active ingredient(s) loading within the microspheres iseasily controlled during matrix synthesis.

The silica microspheres undergo slow in-vivo dissolution (erosion).Hence, the active ingredient release rate is a function of the activeingredient(s) diffusion rate inside the porous microspheres, the activeingredient loading and size of the microspheres.

Prevention of Surface Interaction (and Denaturation) Between the Matrixand the Active Ingredient (Applicable to All Processes).

The substitution of metal alkoxides by organically modified siliconalkoxides leads to the replacement of the hydroxyl groups at the surfaceof the pores by organic moieties (e.g. methyl vinyl, glycidyloxypropylgroups). This prevents interaction between the entrapped bio-moleculesand the surface, and potential degradation of the active ingredient.This is illustrated by the encapsulation of cis-platin in silica gels.The cis-platin reacts with the surface of the silica matrix resulting inthe precipitation of metallic platinum nanoparticles (see FIG. 14). Thesubstitution of 50% of the tetra methoxy-silane (TMOS) bymethyltrimethoxysilane (MTMS) prevents any such precipitation.

Process 1

One process of preparing substantially monodispersed controlled releaseceramic particles typically comprises:

-   -   a) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent where typically the amount of surfactant        is between 5-30 wt. % of the solvent;    -   b) preparing a precursor solution by dissolving a gel precursor,        a catalyst, a condensing agent and a (or several) soluble active        material(s) in a polar solvent comprising water and alcohol        where typically the water to precursor molar ratio is between 2        and 8, the alcohol to precursor molar ratio is between 0 and 16,        the pH is between 1 and 11, and the proportion of active        material is between 0.1-10 mg/g of final metal oxide;    -   c) preparing an emulsion by combining the reverse micelle        solution and the precursor solution where typically the        proportion of reverse micelle solution to precursor solution is        adjusted so that the surfactant to oxide gel precursor molar        ratio is between 0.1-10, more typically a ratio of 0.5-2; and    -   d) forming and aging substantially monodispersed controlled        release ceramic particles, wherein each of said particles has        the active material(s) substantially homogeneously dispersed        throughout the particle, by condensing the precursor in the        emulsion.

Typically the gel precursor is selected from the group consisting of asilica precursor, an alumina precursor and a titania precursor and moretypically the gel precursor is a silica gel precursor.

-   -   Typically step (d) comprises:    -   (d) forming and aging substantially monodispersed controlled        release ceramic particles, wherein each of said particles has        the active material substantially homogeneously dispersed        throughout the particle, the active material is capable of being        released from said particle and the active material in said        particles is incorporated so as to be substantially protected        from degradation until release of the active material from the        particles, by condensing the precursor in the emulsion.

The process may further comprise:

-   -   (e) separating said formed and aged controlled release ceramic        particles from said emulsion.

The process may further comprise:

-   -   (e) removing surfactant from said formed and aged controlled        release ceramic particles.        Process 2

An alternative process of preparing substantially monodispersedcontrolled release ceramic particles typically comprises:

-   -   (a′) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent and a hydrophilic first (or several)        active material(s) where typically the amount of surfactant is        between 5-30 wt % of the solvent and the proportion of active        material(s) is between 0.1-1 wt % of final metal oxide;    -   (b′) preparing a precursor solution by dissolving a gel        precursor, a catalyst, a condensing agent and optionally a (or        several) soluble second active material(s) in a polar solvent        (which is immiscible with the apolar solvent in (a′)) comprising        water and alcohol where typically the water to precursor molar        ratio is between 2 and 8, the alcohol to precursor molar ratio        is between 0 and 16, the pH is between 1 and 11, and the        proportion of second active material is between 0.1-10 mg/g of        final metal oxide;    -   (c′) preparing an emulsion by combining the reverse micelle        solution and the precursor solution; the proportion of reverse        micelle solution to precursor solution is adjusted so that the        surfactant to oxide gel precursor molar ratio is between 0.1-10        where typically this molar ratio is of 0.5-2; and    -   (d′) forming and aging substantially monodispersed controlled        release ceramic particles, wherein each of said particles has        the active material(s) substantially homogeneously dispersed        throughout the particle, by condensing the precursor in the        emulsion.

Typically the gel precursor is a silica gel precursor.

Typically step (d′) comprises:

-   -   (d′) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material        substantially homogeneously dispersed throughout the particle,        the active material is capable of being released from said        particle and the active material in each of said particles is        incorporated so as to be substantially protected from        degradation until release of the active material from the        particle, by condensing the precursor in the emulsion.

The process may further comprise:

-   -   (e′) separating said formed and aged controlled release ceramic        particles from said emulsion.

The process may further comprise:

-   -   (e′) removing surfactant from said formed and aged controlled        release ceramic particles.        Process 3

Another process of preparing substantially monodispersed controlledrelease ceramic particles comprises:

-   -   (a″) preparing a precursor solution by dissolving a gel        precursor (TEOS), an (or several) active material(s) (active        material(s) is (are) soluble in TEOS by itself or in        TEOS/solvent mixture) and optionally a small quantity of solvent        (ethanol);    -   (b″) preparing a condensing solution comprising a catalyst (acid        or base or both sequentially), a condensing agent (H2O) and        optionally a small quantity of solvent (ethanol), said        condensing solution being substantially immiscible with said        precursor solution;    -   (c″) combining the precursor solution and the condensing        solution to form a mixture and preparing an emulsion by        spontaneously emulsifying the mixture in the absence of a        surfactant;    -   (d″) forming and aging substantially monodispersed controlled        release ceramic particles, wherein each of said particles has        the active material(s) substantially homogeneously dispersed        throughout the particle and wherein the active material(s) is        capable of being released from said particle, by condensing the        precursor in the emulsion.

Typically the gel precursor is a silica gel precursor.

Typically step (d″) comprises:

-   -   (d″) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material        substantially homogeneously dispersed throughout the particle,        the active material is capable of being released from each of        said particles and the active material in each of said particles        is incorporated so as to be substantially protected from        degradation until release of the active material from the        particle, by condensing the precursor in the emulsion.

The process may further comprise:

-   -   (e″) removing surfactant from said formed and aged controlled        release ceramic particles.        Process 4

Another process of preparing substantially monodispersed controlledrelease ceramic particles comprises:

-   -   a′″) preparing a reverse micelle solution by mixing a surfactant        with an apolar solvent where typically the amount of surfactant        is between 1-30 wt. % of the solvent;    -   b′″) preparing an hydrophilic solution by dissolving a catalyst,        a condensing agent and a (or several) soluble active material(s)        in a polar solvent comprising water.    -   c′″) preparing an emulsion by combining the reverse micelle        solution and the hydrophilic solution.    -   d′″) adding a gel precursor to this emulsion where typically the        proportion of reverse micelle solution to precursor is adjusted        so that the surfactant to oxide gel precursor molar ratio is        between 0.1-10, more typically a ratio of 5-2; and    -   e′″) forming and aging substantially monodispersed controlled        release ceramic particles, wherein each of said particles has        the active material(s) substantially homogeneously dispersed        throughout the particle, by condensing the precursor in the        emulsion.

The step (d′″) comprises:

-   -   (d′″) adding a silica gel precursor to the emulsion.

Typically step (e′″) comprises:

-   -   (e′″) forming and aging controlled release ceramic particles,        wherein each of said particles has the active material        substantially homogeneously dispersed throughout the particle,        the active material is capable of being released from each of        said particles and the active material in each of said particles        is incorporated within said particle so as to be substantially        protected from degradation until release of the active material        from the particle, by condensing the precursor in the emulsion.

The process may further comprise:

-   -   (e′″) separating said formed and aged controlled release ceramic        particles from said emulsion.

The process may further comprise:

-   -   (e′″) removing surfactant from said formed and aged controlled        release ceramic particles.

FIG. 23 illustrates in block diagram form a preferred process ofpreparing substantially monodispersed controlled release ceramicparticles, typically nanospheres. The preferred process is described indetail below.

Gel Nanosphere Preparation (Applicable Mainly to Process 4)

A reverse micelle solution is prepared by mixing a surfactant (typicallya surfactant which does not substantially interact with the active beingused—e.g. CU(NH₃)₄+ ionic surfactant leads to loss of Cu(NH₃)₄ in thewashing step whereas with Cu(NH₃)₄+ non ionic surfactant loadings of1-35 wt. % Cu have been achieved) with an apolar solvent where typicallythe amount of surfactant is between 5-30 wt. % of the solvent (solutionA). A hydrophilic solution is prepared by dissolving a catalyst, acondensing agent and a (or several) soluble active materials (such as apharmaceutical or radiopharmaceutical tracer e.g. Cu, Pt . . . ) in apolar solvent comprising water (solution B). An emulsion is prepared bycombining the reverse micelle solution (Solution A) and the hydrophilicsolution (Solution B). A gel precursor is added to this emulsion wheretypically the proportion of reverse micelle solution to precursor isadjusted so that the surfactant to oxide gel precursor molar ratio isbetween 0.1-10, more typically a ratio of 0.5-2 whereby the precursorcondenses in the emulsion thereby forming and aging controlled releaseceramic nanoparticles, wherein each of said particles has the activematerial substantially homogeneously dispersed throughout the particle,the active material is capable of being released from each of saidparticles and the active material in each of said particles isincorporated within said particle so as to be substantially protectedfrom degradation until release of the active material from the particle.

FIG. 24 depicts a block diagram showing a preferred washing procedure.In essence an ionic salt such as NaCl solution (e.g. 0.1-10M, typically0.5-5M, more typically 1M) is added in a sufficient quantity todestabilise the emulsion. This destabilised emulsion is then washed anumber of times with an organic solvent (eg NaCl+CHCl₃ and/or bromoformand/or iodoform) which is decanted off. The washed aqueous suspension isthen freeze dried to form a solid in which unaggregated ceramicnanospheres are isolated within a matrix of the NaCl.

It has been found by the inventors that the presence of NaCl protectsthe ceramic particles during the freeze drying process. As indicatedabove as a result of this process the unaggregated freeze driedparticles are isolated in a protective NaCl matrix (other ionic saltsmay be used particularly for non-biological uses but NaCl isparticularly suited for biological applications, especially in vivobiological applications related to mammals including humans). The doped,freeze dried, ceramic nanoparticles may be irradiated, then redispersedin an appropriate amount of water to provide an isotonic solution and,if required, the solution may be injected for in vivo treatment,diagnosis or studies.

EXAMPLES A) Influence of the Sol-Gel Processing Parameters on theRelease of Orange II Example 1 Influence of the Methanol/TMOS andH₂O/TMOS Molar Ratios on the Release Rate of Orange II

A solution of dye was produced by dissolving 0.25 g of4-(2-hydroxy-1-napthylazo) benzene sulfonic acid, sodium salt (i.e.Orange II, Aldrich) in 25 ml of a 0.1M nitric acid solution and dilutingto 250 ml with demineralised water. The final pH of the dye solution was2.

Gels were synthesised by combining tetramethylorthosilicate (TMOS),methanol (MeOH), and the dye solution. The influence of H₂O/TMOS ratio(W) and MeOH/TMOS ratio (D) on the dye release rate was studied by usingthe compositions listed in Table 1. TABLE 1 Compositions of gelssynthesised with different W and D. D = 0 D = 4 D = 8 W = 2 TMOS TMOSTMOS (8.10 ml, (5.00 ml, 33.6 mmol) (3.00 ml, 20.2 mmol) 54.4 mmol) H₂OH₂O H₂O¹ (1.21 ml, 67.2 mmol) (0.73 ml, 40.3 mmol) (1.96 ml, MeOH MeOH109 mmol) (5.44 ml, 134 mmol) (6.54 ml, 161 mmol) W = 4 TMOS TMOS TMOS(8.10 ml, (4.00 ml, 26.9 mmol) (3.00 ml, 20.2 mmol) 54.4 mmol) H₂O H₂OH₂O (1.94 ml, 108 mmol) (1.45 ml, 80.6 mmol) (3.92 ml, MeOH MeOH 218mmol) (4.36, 108 mmol) (6.54 ml, 161 mmol) W = 8 TMOS TMOS TMOS (7.00ml, (4.00 ml, 26.9 mmol) (3.00 ml, 20.2 mmol) 47.0 mmol) H₂O H₂O H₂O(3.88 ml, 215 mmol) (2.91 ml, 161 mmol) (6.78 ml, MeOH MeOH 376 mmol)(4.36 ml, 108 mmol) (6.54 ml, 161 mmol)¹Water is added in the form of the Orange II dye solution.

The resulting mixtures were stirred for 1 h. 4 ml aliquots of thesolutions were transferred to 5 ml screw capped polypropylene vials andplaced at 60° C. in an oven to gel. Once gelation occurred, the sampleswere aged at 60° C. for two more days. For each composition, one gel rodwas set apart to study the release in the wet state and the remaininggel rods were dried at 60° C. for 3 days. In the following, the gel rodsremaining in the wet state will be labelled as “wet gels” while thosedried at 60° C. will be referred to as “dry gels”.

The release of the dye molecule from the gels was performed in 3 ml ofdemineralised water and the evolution of the absorbance with time wasmonitored at a fixed wavelength λ_(max)=485 nm using a UV-visiblespectrophotometer (Lambda 40, Perkin Elmer, USA). The wavelength of 485nm corresponds to the absorbance maximum of Orange II in the visiblespectrum.

The plots of fraction of dye released versus time (FIG. 1) were obtainedby dividing the actual quantity of dye released by the total mass of dyeencapsulated in the gel. For the dry gel, this quantity is calculated bydividing the total quantity of dye in the gel rod by the mass of the geland multiplying it by the mass of the gel sample used in the releaseexperiments. For the wet gel, the fraction released was obtainedexperimentally from the final absorbance.

The release rate of the dye was found to increase with increasing W anddecreasing D. Note that constant release rates were obtained forcompositions 1/8/4 and 1/4/0.

Example 2 Influence of the pH on the Release Rate of Orange II

To study the influence of pH, gels were prepared by adjusting the pH ofthe dye solutions to 1, 2, 4, 7, 9 or 11.

The different dye solutions were produced by dissolving 0.10 g of OrangeII dye in 100 ml of nitric acid (0.1 M) or aqueous ammonia (0.1M) andfurther adjusting, by titration, the pH to the desired value.

The gels were synthesised by mixing 5.51 ml of TMOS (37 mmol), 2.67 mlof dye solution at the appropriate pH (148 mmol of water) and 6 ml ofmethanol (148 mmol). The samples were then aged and dried according tothe procedure described in Example 1. The corresponding release curvesare presented in FIG. 2.

For gel synthesised using acid as a catalyst (FIG. 2-1), the releaserate was found to increase with increasing pH. In contrast, for the gelsynthesised using base as a catalyst, the release was found to decreasewith increasing pH. The maximum release rate was observed at pH=7.

Example 3 Influence of MTMS/TMOS Ratio

Gels were synthesised according to the procedure described in Example 1but substituting 0-50% of TMOS with equimolar quantities ofmethyltrimethoxysilane (MTMS, Fluka). W and D were both fixed to 4,corresponding to 2.67 ml of dye solution at pH=2 (H₂O=148 mmol) and 6.00ml of methanol (148 mmol). TABLE 2 Compositions of gels synthesised withvarious MTMS/TMOS molar ratios. MTMS (mol %)  0% TMOS (5.51 ml, 37.0mmol) 10% TMOS (4.96 ml, 33.3 mmol), MTMS (0.53 ml, 3.70 mmol) 20% TMOS(4.41 ml, 29.6 mmol), MTMS (1.06 ml, 7.41 mmol) 30% TMOS (3.86 ml, 25.9mmol), MTMS (1.59 ml, 11.1 mmol) 40% TMOS (3.31 ml, 22.2 mmol), MTMS(2.11 ml, 14.8 mmol) 50% TMOS (2.78 ml, 18.5 mmol), MTMS (2.64 ml, 18.5mmol)

The corresponding release kinetics are shown in FIG. 3. The release ratewas found to decrease with increasing MTMS content.

Example 4 Influence of the Syneresis Time on the Release Rate of OrangeII

A series of gels was synthesised by varying the syneresis time from 0 to30 days.

A stock solution containing 30.3 ml of TMOS (204 mmol), 14.7 ml ofOrange II dye solution at pH 2 (815 mmol) and 33.0 ml of methanol (815mmol) was stirred for 1 h. 4 ml aliquots of this solution weretransferred to 5 ml screw capped poly-propylene vials and placed in anoven at 60° C. to gel. The resulting gels were further aged at 60° C.for 0, 2, 3, 7, 15 and 30 days. The vials were subsequently uncapped andthe aged gels were dried in the oven at 60° C. for 3 days. The releaseexperiments were conducted following the procedure described inExample 1. The corresponding release curves are presented in FIG. 4.

The release rate was found to increase with syneresis time.

Example 5 Influence of the Drying Temperature and Time on the ReleaseRate of Orange II

A stock solution containing 78.6 g TMOS (516 mmol) and 37.3 g of OrangeII dye solution at pH 2 (2.07 mol of H₂O) was stirred for 1 h. 4 mlaliquots of this solution were transferred to 5 ml screw cappedpoly-propylene vials and placed at 60° C. in an oven to gel. Theresulting gels were further aged at 60° C. for two days. The aged gelswere then dried for 1, 3 or 7 days at ambient (i.e. 22-23° C.), 60° or104° C. The release experiments were conducted following the proceduredescribed in Example 1. The corresponding release kinetics are presentedin FIG. 5.

The release rate was found to decrease with increasing time andtemperature.

B) Influence of Other Parameters on the Release Rate of Orange IIExample 6 Influence of the Environment on the Release Rate of Orange H

Gels were synthesised according to the procedure described in Example 1.The water/alkoxide and the methanol/alkoxide molar ratio were both fixedto 4, corresponding to 2.67 ml of dye solution at pH=2 (148 mmol of H₂O)and 6.00 ml of methanol (148 mmol) for 5.51 ml of TMOS (37 mmol). Thegels were then dried at room temperature for 1 day.

To study the influence of the temperature on the release rate, a knownquantity of gel was immersed in 3 ml of demineralised water and theabsorbance was monitored at a fixed wavelength of 485 nm. One sample waskept at ambient temperature (i.e. 22° C.) and two others were maintainedat 37° C. and 60° C. in thermostated water baths. The correspondingrelease kinetics are presented in FIG. 7. The release rate was found toincrease with increasing temperature.

Example 7 Comparison Between the Release Kinetics of Orange II andMethyl Violet

A methyl violet solution was prepared by dissolving 0.112 g of the dyepowder (Aldrich) in 5 ml of methanol and diluting the resulting solutionwith 100 ml of 0.1M nitric acid. The final pH of the solution wasadjusted to 2. A solution of the Orange II dye was prepared as describedin Example 1.

Two sets of gels were prepared by combining tetramethylorthosilicat-e(TMOS), methanol (MeOH), and each of the dye solutions. W and D wereboth fixed to 4, corresponding to 2.67 ml of dye solution (148 mmol ofH₂O), 6 ml of methanol (148 mmol) and 5.51 ml of TMOS (37 mmol). 4 mlaliquots of these solutions were transferred to 5 ml screw cappedpoly-propylene vials and placed in an oven at 60° C. to gel. Theresulting gels were further aged at 60° C., for 15 or 30 days, beforebeing dried for 2 days at 60° C.

The release rates of the Orange II samples were monitored at a fixedwavelength of 485 nm while the release rates of the methyl-violetsamples were monitored at 584 nm (corresponding to the absorption peakof methyl-violet in the visible spectrum). The corresponding releasekinetics are presented in FIG. 8.

The release rate was found to be significantly smaller for the largerdye molecule (i.e. methyl violet)

C) Parameters Controlling the Size of Microspheres Example 8 Synthesisof Microspheres with Different Size by Changing the Emulsion Solvent

A sol-gel solution (solution A) was prepared by combining 5.21 ml ofTMOS (35 mmol), 2.52 ml of Orange II dye solution at pH=2 (as perExample 1) (140 mmol of H₂O) and 6.19 ml of methanol (153 mmol). Theresulting solution was stirred for 30 min. at 300 rpm and left to agefor 1 day at room temperature.

15.08 g of sorbitan monooleate was dissolved in 170 ml of kerosene andhomogenised using a high speed blender (1200 rpm for 45 s) to form aclear solution (solution B). Solution A was then added to solution B andthe resulting emulsion was stirred at 500 rpm for 1 h. The resultingsuspension of microspheres was then filtered and rinsed three times withcyclohexane to remove the surfactant. The resulting microspheres werethen dried for 1 day at room temperature before further drying at 60° C.for 3 days. The procedure was repeated using hexane, heptane, octane,decane, dodecane and cyclohexane as the emulsion solvent. Selectedscanning electron micrographs of the dried microspheres obtained usingthese solvents are presented in FIG. 9.

The average size of the microspheres was found to decrease withdecreasing polarity of the solvent (i.e. heptane>octane>dodecane>-;cyclohexane).

Example 9 Influence of the Surfactant Chain Length on the Size of theMicrospheres

To study the influence of the surfactant chain length on the size of themicrospheres, samples were prepared according to the procedure describedin example 8 but with sorbitan monooleate replaced by sorbitanmonolaurate (12.1 g). As in example 8, a series of experiments wasperformed using various solvent, such as hexane, octane, decane anddodecane. An example of the influence of the surfactant chain length onthe microspheres size is presented in FIG. 10. In this instance,increasing the hydrophobic chain length decreases the size of themicrosphere. However, it should be noted that whether this effect isobserved or not will be dependent on the particular surfactant/non-polarsolvent combination used. Whether or not the effect is present for aparticular surfactant/non-polar solvent combination can be readilychecked by routine experiment.

Example 10 Synthesis of Nano-Spheres Using AOT as the Surfactant

4.46 g of AOT (10 mmol) was dissolved in 100 ml of cyclohexane and mixedwith 1.26 g of Orange II dye solution at pH=2 (70 mmol of H₂O) to form astable micro-emulsion. 2.66 g of TMOS (17 mmol) was then added to themicroemulsion and the resulting mixture was stirred for 1 day.

The resulting precipitate was filtered and washed with cyclohexane. Thewashed solid was then dried at room temperature. The correspondingscanning electron micrograph is shown in FIG. 11. In this case,nanospheres are produced (i.e. size.apprxeq. 100 nm) instead ofmicrospheres.

Example 11 Synthesis of Microspheres with Different Sol-Gel Chemistry

The microspheres were prepared according to the procedure given inexample 8 but using three different sol-gel chemistries. In each cases,the sol-gel solutions (solution A in example 8) were prepared by mixing5.33 g of TMOS (35 mmol) with 4.9 g of methanol (153 mmol) and adding2.52 g of Orange II dye solution (140 mmol of H₂O). In the first sample,the dye solution was prepared at pH=2, while in the second, the dyesolution was prepared at pH=11. In the third case TMOS was partiallysubstituted by MTMS (i.e. 20 mol %). The corresponding release curvesare presented in FIG. 12-1. An example of the influence of pH on theinternal microstructure of the microspheres is given in FIG. 12-2. Themicrospheres produced at pH=2 present a smooth surface which correspondto a microporous internal structure while the microspheres produced atpH=11 possess a rough surface denoting a mesoporous internal structure.FIG. 12-1 and FIG. 13 show that the internal structure of the spherestrongly influences their release rate.

Example 12 Influence of the Drying Temperature on the Release Rate ofMicrospheres

Microspheres containing orange II dye were synthesised according to theprocedure described in example 8. The resulting microspheres were thendried at different temperatures from ambient to 100° C. for 2 days. Thecorresponding release kinetics are presented in FIG. 13. As for example5, the release rate decreases with increasing drying temperature.

Example 13 Prevention of Drug Degradation by Surface Functionalisation

A solution of cis-platin (Cis Pt(NH₃)₂Cl₂) was prepared by dissolving50.0 mg of cis-platin in 50 ml of 0.01M HCl solution and sonicating thesolution for 15 minutes using a Branson 3200 sonication bath.

A solution containing 20 ml of TMOS (134 mmol), 9.69 ml of cis-platinsolution (538 mmol of water) and 21.8 ml of methanol (538 mmol) wasstirred for 30 minutes. 4 ml aliquots of the solution were transferredto 5 ml screw capped poly-propylene vials and placed in an oven at 60°C. to gel. Once gelation occurred the samples were aged at 60° C. for 15days. The cap was then removed and the samples were allowed to dry for 3days at 60° C.

An identical procedure was used to prepare gels from a solutioncontaining 3 ml of TMOS, 2.88 ml of MTMS and 2.91 ml of cis-platinsolution.

After 3 days of aging at 60° C. the gels prepared from TMOS started todarken, ultimately yielding a black gel after 15 days aging. In thecontrast the gels prepared from MTMS/TMOS mixtures remained perfectlytransparent even after 15 days aging at 60° C. The two dry gels weresubsequently examined by transmission electron microscopy using a JEOL201 OF field emission gun microscope. The black gel was found to containsmall platinum colloids (.apprxeq. 50-80 nm in size) dispersedthroughout the silica matrix (see FIG. 14). No such colloids were foundto be present in the MTMS modified gels suggesting that the surfacemethyl groups present in the MTMS functionalised gels minimizesinteraction of the cis-platin with the matrix and its associatedprecipitation.

Example 14 Influence of the Presence of MTMS on the Release ofCis-Platin and Cycloheximide

A solution of cycloheximide was prepared by dissolving 25.0 mg ofcycloheximide in 25 ml of 0.01M HCl solution (pH=2). A solution ofcis-platin (1 g/l) was prepared by dissolving 50.0 mg of cis-platin in50 ml of 0.1M HCl solution and sonicating the resulting solution for 15minutes.

The first series of samples was prepared by mixing 5.51 ml of TMOS (37mmol), 2.67 ml of either drug solutions (148 mmol of H₂O) and 6 ml ofmethanol (148 mmol). 4 ml aliquots of the solutions were transferred to5 ml screw capped poly-propylene vials and placed in an oven at 60° C.to gel. Once gelation occurred the samples were aged at 60° C. for 7days. The cap was then removed and the samples were allowed to dry for 3days at 60° C.

A second series of samples was prepared by combining 3 ml of TMOS (20mmol), 2.88 ml of MTMS (20 mmol) and 2.91 ml of the respective drugsolution (161 mmol of H₂O). These samples were processed as describedabove.

The release of cycloheximide from a known quantity of gel wasinvestigated in 3 ml of demineralised water and the absorbance wasmonitored at a fixed wavelength, .λ_(max)=201 nm. The release ofcis-platin from a known quantity of gel was investigated in 3 ml of 0.9%NaCl and the absorbance was monitored at a fixed wavelength, λ_(max)=300nm. The corresponding release kinetics are presented in FIGS. 15-1 and15-2.

As expected (cf. example 7), the release rate was found to be greaterfor the smaller drug molecule (i.e. cis-platin). As for Orange II (cf.example 3), substitution of TMOS by MTMS led to a decrease in therelease rate of both drugs.

Example 15 Synthesis of Cu Doped Silica Nanoparticles Using Process 4

A copper tetraamine solution (i.e. solution 1) was prepared bydissolving Cu(NO₃)₂.3H₂O (4.38 g, 18 mmol) in 10 ml of concentratedammonia solution and diluting the resulting solution to 100 ml withdistilled water. Triton X-114 (10.72 g, 20 mmol) was dissolved in 100 mlof toluene, and a microemulsion was subsequently produced by adding 5.76ml of solution 1 (32 mmol equivalent of H₂O) and homogenising theresulting mixture by shear-mixing at 8000 rpm for 1 min. The emulsionwas then stirred at 300 rpm and 0.3 ml of TMOS (2 mmol) was added. Afterstirring for 90 minutes, 50 ml of a 1M solution of NaCl was added to theemulsion and the resulting suspension was transferred to a decantationfunnel. After 12 hours the emulsion had separated into two phases. Theaqueous (bottom) phase was extracted and 100 ml of toluene was addedbefore re introducing the mixture into a clean decantation funnel. Thisprocedure was repeated several times, until the top organic phase hadbecome transparent to the naked eye. The final washed aqueous particlesuspension was then left to settle overnight, and the supernatant wasfinally removed to minimise the volume of liquid to be removed duringsubsequent freeze-drying.

The nanoparticle suspension was freeze-dried by plunging the flaskcontaining the suspension into liquid nitrogen, and subliming the waterby pumping at a background pressure of 10 mTorr. The resulting drypowder was composed of nanoparticles encapsulated in a matrix of sodiumchloride (see FIG. 17-1). This powder could be easily redispersed inwater, yielding particles with an average particle size around 200 nm(see FIG. 17-2) and a narrow size distribution (see FIG. 17-3).

Example 16 Synthesis of Cis-Platin Doped Nanoparticle Using Process 4

A cis-platin solution (solution 2) was prepared by dissolving 0.16 gcis-platin (0.53 mmol) in 100 ml of a dilute ammonia solution (10 wt %).Triton X-114 (10.74 g, 20 mmol) and 11.52 ml of solution 2 (32 mmolequivalent of H₂O) were added sequentially to 100 ml of toluene, and theresulting micro-emulsion was homogenised by shear-mixing at 8000 rpm for1 minute. The emulsion was then stirred at 300 rpm and 0.3 ml of TMOS (2mmol) was added. After stirring for 90 minutes, 50 ml of a 1 M NaClsolution was added to the emulsion and the resulting suspension wastransferred to a decantation funnel. The suspension was then washed andfreeze-dried according to the procedure described in Example 15.

Example 17 Synthesis of Ultra-Small (i.e. <100 nm) Copper Doped SilicaParticles

A copper tetraamine solution (i.e. solution 3) was prepared bydissolving 40 mg of Cu(NO₃)₂.3H₂O (0.17 mmol) in 5 ml of concentratedammonia (28 wt % NH₃). Triton NP-9 (7.77 g, 12.6 mmol) and 0.710 ml ofsolution 3 (23.5 mmol equivalent of H₂O) were added sequentially to 100ml of cyclohexane, and the resulting micro-emulsion was homogenised byshear-mixing at 8000 rpm for 1 minute. The emulsion was then stirred at500 rpm and 0.796 ml of TEOS (3.6 mmol) was added. After continuousstirring for 24 hours, 50 ml of demineralised water was added to theemulsion and the resulting suspension was transferred to a decantationfunnel. After standing for 12 hours, the emulsion had separated into twophases. The aqueous phase was extracted, mixed with cyclohexane (100 ml)and transferred to a clean decantation funnel. This procedure wasrepeated several times, until the top organic phase was transparent tothe naked eye. A TEM micrograph (FIG. 18-1) of the dried particlesindicates that their diameter is ca. 50 nm. Photon correlationspectroscopy of the particle suspension confirmed that the averageparticle size in solution was 51 nm (FIG. 18-2).

Example 18 Influence of the Surfactant to Alkoxide Molar Ratio (S) onthe Average Size of Cu Doped Silica Nanoparticles

Nanoparticles were synthesised according to the procedure in examples 15using the following emulsion compositions:

3 S R Triton X-114 TMOS Solution 1 2 16 18 g (35 mmol) 2.66 g (17 mmol)10 ml (559 mmol) 10 16 22.49 (44 mmol) 0.665 g (4.3 mmol) 12.6 ml (700mmol)

Here, S and R refer to the surfactant-to-alkoxide molar ratio and thewater-to-surfactant molar ratio, respectively. The resulting particleswere filtered and analysed by SEM (see FIG. 19), which revealed that anincrease in S leads to a corresponding decrease in the particle size.

Example 19 Influence of the Water to Alkoxide Molar Ratio on the AverageSize of Cu Doped Silica Nanoparticles

Nanoparticles were synthesised according to the procedure in examples 15using the following emulsion compositions:

4 S R Triton X-114 TMOS Solution 1 10 8.8 21.54 g (40 mmol) 0.596 ml (4mmol) 6.34 ml (352 mmol) 10 1.6 21.54 (40 mmol) 0.596 ml (4 mmol) 1.15ml (64 mmol)

The corresponding freeze-dried powders were re-suspended in distilledwater and characterised by PCS (see FIG. 20). Both particle sizedistributions exhibited a peak at ca. 150 nm, although thepolydispersity increased significantly with decreasingwater-to-surfactant mole ratio.

Example 20 Influence of the Concentration of NaCl on the Quantity ofSurfactant Retained on the Washed Particles

Nanoparticles were synthesised according to the procedure described inExample 15, using 21.44 g of Triton X-114 (40 mmol), 0.596 ml of TMOS (4mmol) and 11.53 ml of solution 1 (640 mmol equivalent of H₂O). Afterformation of the nanoparticles, the sample was separated into twobatches. A 50 ml aliquot of distilled water was added to the firstbatch, while 50 ml of 0.1M NaCl solution was added to the second. Thetwo suspensions were then washed according to the procedure described inExample 15 and subsequently filtered and dried overnight at 60° C. Asample of each dry powder was then characterised using thermal analysis.The corresponding weight losses associated with desorption/pyrolysis ofthe surfactant are shown in the following table:

5 Residual Surfactant (wt %) Without NaCl 3.8 With 0.1 M NaCl 2.4

Example 21 Synthesis of Particles by Process 3

A 10 ml sample of TEOS (45 mmol) was dissolved in 40 ml of ethanol and0.87 ml of an Orange II dye solution at pH=2 (prepared according to theprocedure outlined in Example 1) was then added. The resulting solutionwas stirred for 90 minutes, before adding 0.87 ml of an Orange II dyesolution at pH=9.05. The mixture was stirred for an additional 90minutes, prior to the drop-wise addition of 200 ml of dilute ammoniasolution (3 wt %). The resulting suspension was aged quiescently for 12hours and then centrifuged at 5000 rpm for 15 minutes. The orange solidthus obtained was finally dried at 60° C. for 12 hours. A SEM micrographof the resulting powder is presented in FIG. 21.

Example 22 Synthesis of Copper Doped Transition Metal Oxide Nanospheres

A copper tetraamine solution (i.e. solution 4) was prepared bydissolving 8.45 g of Cu(NO₃)₂.3H₂O (35 mmol) in 40 ml of concentratedammonia solution (28 wt % NH₃) and diluting the resulting solution to100 ml with distilled water. Triton NP-9 (19.5 g, 32 mmol) was dissolvedin 150 ml of cyclohexane and a microemulsion was subsequently producedby adding 1.125 ml of solution 4 (62 mmol equivalent of H₂O) andhomogenising the resulting mixture by shear-mixing at 8000 rpm for 1minute. The microemulsion was then maintained with stirring at 500 rpm.

In a dry nitrogen glove box, 1.83 g (6.4 mmol) of titanium isopropoxide(or 2.78 ml of Zr n-propoxide or 1.639 ml of Al sec-butoxide) wasdissolved in 5 ml of cyclohexane. This solution was then added, outsidethe glove box, to the stirred NP-9/solution 4/cyclohexane emulsion andthe resulting mixture was stirred for 2 hours at 500 rpm. A 100 mlaliquot of 1M NaCl was then added to the suspension, and the aqueouslayer was washed and freeze-dried according to the procedure outlined inExample 15.

Example 23 Synthesis of TiO,/SiO, Mixed Oxide Particles Doped withOrange H by Process 1

Solution 5 was prepared by mixing 0.05 g of Orange II with 20.0 ml ofconcentrated (70%) nitric acid and diluting with demineralised water toa total volume of 100 ml. The concentrations of HNO₃ and Orange II inthe final solution were 2.22 M and 0.5 mg/ml, respectively.

A solution containing 1.53 ml of ethanol and 0.47 ml of solution 5(EtOH:H₂O:HNO₃ mole ratio=1:1:0.04) was added dropwise to a mixture ofTEOS (5.92 ml, 26.5 mmol) in ethanol (1.53 ml), and the resultingmixture agitated in a Cole Palmer Model 8892 ultrasonic bath for 15minutes. An aliquot of titanium tetraisopropoxide (1.53 ml, 5.2 mmol)was then added, and the complex alkoxide mixture was sonicated for anadditional 15 minutes, and then refluxed for four hours.

A 10 g sample of sorbitan monooleate (23 mmol) was mixed with 100 ml ofkerosene in a 250 ml conical flask and stirred for ca. 30 minutes with amagnetic follower, to ensure complete dissolution of the surfactant. A1.40 ml aliquot of solution 5 was added dropwise to the stirredsolution, followed by addition of the complex alkoxide mixture. Theresulting sample was stirred for 110 minutes, yielding SiO₂/TiO₂ mixedoxide microspheres. The final product was filtered, washed with three 20ml aliquots of kerosene to remove residual surfactant, dried for 24hours at ambient temperature and then dried overnight at 60° C. An SEMmicrograph of the resulting microspheres is shown in FIG. 22.

It should be appreciated that various other changes and modificationsmay be made to the embodiment described without department from thespirit and scope of the invention.

1. A process of preparing controlled release ceramic particles,comprising: (a) providing a precursor solution that is the product ofcombining a gel precursor selected from the group consisting of asilica-based gel precursor, an alumina-based gel precursor, a titaniumdioxide-based gel precursor, an iron oxide-based gel precursor, azirconium dioxide-based gel precursor and a combination thereof, anactive material, and optionally a solvent; (b) providing a condensingsolution that is the product of combining a catalyst, a condensingagent, and optionally a solvent, wherein said condensing solution issubstantially immiscible with said precursor solution; and then (c)combining said precursor solution and said condensing solution to form amixture and spontaneously emulsifying said mixture in the absence of asurfactant, such that ceramic particles form that (i) contain saidactive material(s) and (ii) are porous to the extent of allowingcontrolled release of said active material(s), whereby the activematerial is substantially homogeneously dispersed within each of theparticles and throughout the particles.
 2. The process of claim 1,wherein the condensing agent is water.
 3. The process of claim 1,wherein the solvent in step (a) and (b) are same or different.
 4. Theprocess of claim 1, wherein the gel precursor is selected from the groupconsisting of a silica precursor, an alumina precursor, a titaniaprecursor, and a combination thereof.
 5. The process of claim 4, whereinthe gel precursor is a silica precursor.
 6. The process of claim 5,wherein said silica precursor is selected from the silicates, thesilsequioxanes, poly-silsequioxanes, the silicon alkoxides,functionalized alkoxides, and a combination thereof.
 7. The process ofclaim 5, wherein said silica is biodegradable and biocompatible.
 8. Theprocess of claim 1, wherein said catalyst is selected from sulfuricacid, phosphoric acid, HCl, HNO₃, acetic acid, tartaric acid, succinicacid, salicylic acid, NaOH, KOH, ammonium hydroxide, Ca(OH)₂ and acombination thereof.
 9. The process of claim 1, wherein said activematerial is selected from pharmaceuticals for human applications,hormones, proteins, drugs for veterinarian applications, fertilizers,pesticides, herbicides, insecticides, biocides, and perfumes.
 10. Theprocess of claim 1, wherein the precursor solution has a pH in the rangeof 1 to
 14. 11. The process of claim 1, further comprising (d) removingsolvent from the ceramic particles and then (e) drying the ceramicparticles.
 12. The process of claim 1, comprising bringing the dropletsinto contact with an aqueous solution of an ionic salt such that theceramic particles are dispersed into the aqueous solution.
 13. Theprocess of claim 12, wherein the suitable ionic salt is selected fromNaCl, KI, KBr, NaI, LiCl, LiBr, LiI, CaCl₂, MgCl₂, NH4NO₃, NaNO₃, KNO₃,LiNO₃, and a combination thereof.
 14. The process of claim 12, furthercomprising freeze drying the aqueous solution to form a solid comprisedof unaggregated ceramic particles within a matrix of the ionic salt. 15.An assemblage of controlled release ceramic particles that is theproduct of a process according to claim
 1. 16. An assemblage ofcontrolled release ceramic particles that is the product of a processaccording to claim
 2. 17. An assemblage of controlled release ceramicparticles that is the product of a process according to claim
 3. 18. Anassemblage of controlled release ceramic particles that is the productof a process according to claim
 4. 19. An assemblage of controlledrelease ceramic particles that is the product of a process according toclaim
 13. 20. An assemblage of controlled release ceramic particles thatis the product of a process according to claim 14.